Total Syntheses of Epothilones A and B

Abstract

Convergent, stereocontrolled total syntheses of the microtubule-stabilizing macrolides epothilones A (2) and B (3) have been achieved. Four distinct ring-forming strategies were pursued (see Scheme ). Of these four, three were reduced to practice. In one approach, the action of a base on a substance possessing an acetate ester and a nonenolizable aldehyde brought about a remarkably effective macroaldolization see (89 → 90 + 91; 99 → 100 + 101), simultaneously creating the C2−C3 bond and the hydroxyl-bearing stereocenter at C-3. Alternatively, the 16-membered macrolide of the epothilones could be fashioned through a C12−C13 ring-closing olefin metathesis (e.g. see 111 → 90 + 117; 122 → 105 + 123) and through macrolactonization of the appropriate hydroxy acid (e.g. see 88 → 93). The application of a stereospecific B-alkyl Suzuki coupling strategy permitted the establishment of a cis C12−C13 olefin, thus setting the stage for an eventual site- and diastereoselective epoxidation reaction (see 96 → 2; 106 → 3). The development of a novel cyclopropane solvolysis strategy for incorporating the geminal methyl groups of the epothilones (see 39 → 40 → 41), and the use of Lewis acid catalyzed diene−aldehyde cyclocondensation (LACDAC) (see 35 + 36 → 37) and asymmetric allylation (see 10 → 76) methodology are also noteworthy.

Total Syntheses of Cochliomycin B and Zeaenol

“…[23] Dess-Martin oxidation of the primary alcohol in 14 generated aldehyde 15, which was subjected to homologation with (methoxymethyl)triphenylphosphorane in the presence of tBuOK to afford methyl enol ether 16 in 77 % yield. [24] To our surprise, the subsequent hydrolysis of 16 with mercury acetate under previously reported reaction conditions [25] provided an unexpected elimination product (α,β-unsaturated aldehyde). By using a modified procedure, [26] we were pleased to find that treatment of the methyl enol ether 16 with mercury acetate at 0°C in THF/H 2 O (v/v, 4:1) followed by the addition of 8 % KI solution gave aldehyde 17 in 75 % yield.…”

Functionalisation of Macroheterocycles with Preserving and Changing Their Sizes

“…For example, the cyclopropanation reaction is applicable in case of enantiomeric pure R-muscone (49) that is an odorous substance (muscus) isolated from glands of musk deer Moschus moschiferus. [46,47] Asymmetrically catalysed cyclization of 14-pentadecinal (50) consisting in hydroboration of its triple bond followed by transmetalation and interaction with the aldehyde functional group in the presence of (-)-3-exo-(dimethylamino) isoborneol (51) yielded E-allyl alcohol (52) with high (92% ee) enantiomeric purity. Hydroxy-directed cyclopropnation by the Denmark method followed by recrystallization yielded the sole diasterereomer of alcohol (53), the Swern oxidation of which and reduction of the cyclopropyl functional group completed the synthesis (Scheme 15).…”

“…[45] Two-step synthesis of mono-N-substituted cyclen (47) with the carbamide side chain consisting in direct functionalization of cyclen (31) up to trisubstituted derivative (48) and its treatment with butyl isocyanate (Scheme 14) is an illustration of correlations between mono-and trisubstituted azacrowns. [40] The literature describes numerous examples of synthesis, in which additional fragments to the already prepared Macroheterocycles Functionalization Accompanied by Preservation and Changing Their Size dioxirane (DMDO) in synthesis of epothilone A and B, [51] their analogues, [52] and antibiotic erythromycin derivatives A. [53] Thus, synthesis of erythronolide A (54) derivatives that are macroheterocycles (55-58) with potentially antibiotic properties [53] was carried out by the interaction between DMDO and cyclic bis-allenes (59) and (60) (61) and (62).…”

Metátese de olefinas aplicada ao fechamento de anéis: uma ferramenta poderosa para a síntese de macrociclos naturais

“…Assim, duas outras estratégias alternativas permitiram contornar o problema da estereosseletividade com sucesso, entre elas, a criação de junção do anel ao nível da ligação simples C9-C10 (Esquema 14). Depois de insucessos iniciais com os catalisadores de Schrock 1 e de Grubbs-I 3 e devido ao grande impedimento estéreo dos substituintes na vizinhança do sítio da reação no substrato 51 52 , somente o uso do catalisador de Grubbs-II 5, por Sun e Sinha, permitiu concretizar esta abordagem, produzindo o macrolido 52 (R = Me) em 89% de rendimento 55 . A mistura 1:1 de isômeros Z/E foi posteriormente hidrogenada e transformada em epotilona B.…”